NKX2-8 deletion-induced reprogramming of fatty acid metabolism confers chemoresistance in epithelial ovarian cancerResearch in context
Jinrong Zhu,
Geyan Wu,
Libing Song,
Lixue Cao,
Zhanyao Tan,
Miaoling Tang,
Ziwen Li,
Dongni Shi,
Shuxia Zhang,
Jun Li
Affiliations
Jinrong Zhu
Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, China; Department of biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, China
Geyan Wu
Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, China
Libing Song
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, China
Lixue Cao
Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, China; Department of biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, China
Zhanyao Tan
Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, China; Department of biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, China
Miaoling Tang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, China
Ziwen Li
Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, China; Department of biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, China
Dongni Shi
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, China
Shuxia Zhang
Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, China; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
Jun Li
Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, China; Department of biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, China; Corresponding author at: Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
Background: Aberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2–8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC). Methods: The deletion frequency and expression of NKX2–8 in 144 EOC specimens were assayed using Fluorescence in situ hybridization and immunochemical assays. The effects of NKX2–8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2–8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays. Findings: NKX2–8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2–8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPT1A and CPT2. Loss of NKX2–8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2–8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC. Interpretation: Our results demonstrate that NKX2–8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2–8-deleted EOC. Fund: This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities. Keywords: NKX2–8, Chemoresistance, Fatty acid oxidation, Metabolic reprogram, Epithelial ovarian cancer
